Aminocyclobutane derivatives, method for preparing same and the use thereof as drugs

ABSTRACT

The present inventions concerns derivatives of aminocyclobutane, particularly as NMDA receptor antagonists, their application in human therapy and their method of preparation. 
     These compounds correspond to the general formula (1): 
                         
wherein:
         X 1  represents a hydrogen atom or fluorine atom;   X 2  is a hydrogen atom or fluorine atom or chlorine atom;   R1 represents a hydrogen atom or fluorine atom or chlorine atom or methyl group or methoxy group or cyano group;   R2 represents independently or together a methyl group or ethyl group.

The present invention concerns derivatives of aminocyclobutane as wellas their method of preparation and their use in human therapy.

Glutamate receptors of the NMDA subtype (N-methyl-D-aspartic acid) areionotropic receptors, mainly permeable to Ca⁺⁺ ions. Physiologically,their activation triggers the opening of an ion channel and theproduction of an incoming current which is only slowly inactivated.Stimulation of this receptor requires the simultaneous presence ofglutamate (endogenous agonist) and glycine or D-serine (endogenousco-agonists) as well as depolarisation of the plasma membrane initiatedby non-NMDA currents. The NMDA receptors are widely spread throughoutthe central nervous system and are also present at the periphery. Theyare found in the neurones, astrocytes and oligodendrocytes (Karadottiret al., 2005, Nature, 438, 1162-1166). At the neuronal level, they arelocated mainly in the post-synapse but also in extra-synaptic regionsalong the axons. The NMDA receptors play a key role in communication andin neuronal plasticity as well as in excitotoxicity.

The physiological activity of the NMDA receptors is essential for normalneuronal function (Chen and Lipton, 2006, J. Neurochem., 97, 1611-1626).On the other hand, over activation of these receptors is involved bothin acute neuronal disorders, for example strokes or cranial traumas, andin chronic stress conditions, for example neurodegenerative disorders.It is also one of the main causes of hyperexcitation leading to epilepsyseizures. There are numerous pathologies considered to be associatedwith NMDA receptor hyperactivity and therefore potentially sensitive toNMDA antagonists. The following can be given as examples: epilepsy,neurodegenerative disorders such as Huntington's disease, Parkinson'sdisease, Alzheimer's disease, strokes, amylotrophic lateral sclerosis ormultiple sclerosis, AIDS-related dementia, anxiety, depression and painsyndromes.

In the present invention, the Applicant focuses in particular on theanti-depressant and analgesic properties of NMDA receptor antagonists offormula (1).

In the context of the present invention, the term “chronic pain”designates painful syndromes which progress over a period of more thanthree months but whose severity can vary over the course of time. On theother hand, the term “acute pain” designates pain which lasts less thanthree months.

Within the scope of the present invention, pain is defined as anabnormal, unpleasant, even distressing, sensory and emotional experiencewhich is perceived and integrated at the highest level of the cerebralcortex, which gives it an emotional and affective nature. By“analgesia”, we refer to a decrease in the intensity of the pain felt inresponse to a painful stimulus. By “analgesic medication” (or“analgesics”), we refer to a medication which relieves or suppresses thepain without leading to a loss of sensation or consciousness.

Pain of differing aetiologies requires different therapeutic strategies.In general, there are several categories of pain depending on themechanisms involved:

-   -   pain due to excessive nociception resulting from lesions or        excitation (for example inflammation) of the peripheral or        visceral tissues;    -   neuropathic (or neurogenic) pain is related to a lesion or to        dysfunctioning or disruption of the somatosensory system; it        differs from nociceptive pain in that it has a different        semiology;    -   psychogenic (or idiopathic pain) is pain which exists in the        absence of lesions. The physiological mechanisms of this type of        pain are not clearly defined. It is generally resistant to        analgesics.

Nevertheless, certain pains have characteristics that are common toseveral types of pain. For example, this is the case for lower back orcancer pain which present in the form of pain caused by excessivenociception, or in the form of neuropathic pain or, in most cases, amixture of the two.

Depression is defined in psychiatry as a mood disorder. It ischaracterised by a loss of motivation associated or not with differentsymptoms such as hopelessness, low self-esteem, anxiety, anguish and, inextreme cases, hallucinations. It is often multi-factorial and generallyhas multiple causes.

It is reported that approximately 7% of Europeans suffer from depressionand that a third of these are resistant to clinically usedantidepressants. The cost of depression in the 15-44 year old age groupfor society is among the highest of all known pathologies. One objectiveof the present invention is to describe new NMDA antagonists which haveadvantageous properties in this indication for which existing treatmentsare not entirely satisfactory.

It has been shown in mice that chronic administration of antidepressantswhich have different mechanisms of action (monoamine oxidase inhibitors,tricyclics, serotonin reuptake inhibitors (SSRI), or mixed serotonin andnoradrenalin reuptake inhibitors) modifies the distribution and densityof the NMDA receptors. In rats, acute administration by intraperitonealroute of ketamine, an NMDA receptor antagonist, reduces the immobilitytime in the forced swimming test, a recognised pre-clinical model fordetecting the antidepressant activity of molecules. In addition, recentstudies indicate that ketamine has antidepressant properties in humans.Thus administration of a single sub-anaesthetic dose of ketamine byintravenous route to patients with resistant depression significantlyimproves their condition and this just 2 hours after injection. Theantidepressant effects obtained moreover last over a week (Zarate etal., 2006, Arch. Gen. Psychiatry, 63, 856-864). The rapidity of thisaction contrasts with the time taken for a reaction to occur withconventional antidepressants, in other words first-generationtricyclics, and the SSRIs or SNRIs which require several weeks oftreatment before any beneficial effect is obtained. It therefore seemsthat NMDA receptor antagonists, and in particular ketamine, areeffective in the treatment of depression, especially in the treatment ofdepression resistant to existing medications.

The therapeutic requirements of pain treatment are considerable. Infact, an incalculable number of individuals suffer from acute pain andover one in five adults both in Europe and the United States suffer fromchronic pain (Johannes et al., 2010, J. Pain, 11, 1230-1239). The objectof the present invention is to describe the advantageous analgesicproperties that the compounds of formula (1) possess as well as thetherapeutic perspectives they open up in the treatment of acute andchronic pain.

Many studies on animals and humans have shown that NMDA receptorantagonists such as ketamine can alleviate many aetiological types ofpain such as, for example, neuropathic, postoperative or cancer pain(Cohen et al., 2011, Adv. Psychosom. Med., 30, 139-161). Thus ketamineby intravenous route reduces neuropathic pain in patients resistant totreatment by conventional antidepressants. It also improves allodyniaand hyperalgia in patients with CRPS (complex regional pain syndrome)(Finch et al., 2009, Pain, 146, 18-25). As an adjuvant, perioperativeadministration of a low dose of ketamine reduces the consumption ofanalgesics and limits acute morphine tolerance following surgery (Eliaet Tramer, 2005, Pain, 113, 61-70). As preventive treatment, ketamineand dextromethorpan (another NMDA antagonist) improve the management ofpostoperative pain (Muir, 2006, Current Opinion in Pharmacology, 6,53-60). Ketamine also seems to prevent the occurrence of chronicpostoperative pain. (Wilder-Smith et al., 2002, Pain, 97, 189-194). Theresults obtained with other NMDA antagonists such as amantadine or MK-81in neuropathic pain are nonetheless non-conclusive (Muir, 2006, alreadycited).

Opening of the NMDA channels causes an increase in intracellular calciumwhich activates, among others, NO synthetase and type II cyclooxygenase,leading to prostaglandin synthesis (PGs). By inhibiting the PGs,especially PGE2, NMDA antagonists thus have a direct impact on theregulation of inflammatory conditions (Beloeil et al., 2009, Anesth.Analg., 109, 943-950). This complementary anti-inflammatory activity ofthe NMDA antagonists can be advantageous in the treatment of acute orchronic pain of inflammatory origin. Similarly, NMDA receptors areexpressed in the chondrocytes and contribute to the mechanical functionof cells (Salter et al., 2004, Biorheology, 41, 273-281). In particular,they appear to be involved in their proliferation and in inflammationleading to the destruction of joint cartilage (Piepoli et al., 2009,Osteoarthritis and Cartilage, 17, 1076-1083). As the latter is notregenerated in adults, use of an NMDA antagonist therefore seems to beparticularly advantageous in preventing or slowing down the destructionof joint cartilage that accompanies certain pathological conditions,such as, for example, inflammatory monoarthritis, rheumatoid arthritis,septic arthritis, osteoarthritis, rheumatoid arthritis, gout,spondylarthritis, acute abarticular rheumatism.

Nevertheless, the clinical usefulness of NMDA antagonists in humans islimited by their unwanted effects, in particular on the central nervoussystem, and especially in the course of repeated treatment. Among theside effects of NMDA antagonists, we can cite for example:hallucinations, confusion, personality disorders, nightmares, agitation,lack of concentration, mood changes, convulsions, sedation, somnolence,nausea (Aarts et Tymianski, 2003, Biochem. Pharmacol., 66, 877-886).These side effects result from the fact that NMDA antagonists block notonly the excessive activation of the glutamate/NMDA system but alsodisrupt its normal physiological function. It therefore appears to beessential in practice to improve the risk-benefit ratio of clinicallyavailable NMDA antagonists.

When the type of pain to be treated is suitable, for example in the caseof arthritis, the risk-benefit ratio of the NMDA antagonist can beimproved by limiting its action on the central nervous system, forexample by means of topical application. The concentration of thecompound in the target tissue is therefore very much higher than itsconcentration in the blood, thus reducing the risk of toxicity.Consequently, several NMDA antagonists have been studied by epidural ortopical route. Ketamine applied locally has been shown to be effectivein the treatment of neuropathic pain not alleviated by conventionalmedications. Different associations of an NMDA antagonist and one ormore other analgesic agents have also been studied in local application.For example, ketamine or other NMDA antagonists have been combined withantidepressants or antihypertensives (U.S. Pat. No. 6,387,957);anti-epileptics (WO 03/061656, WO 98/07447, WO 99/12537, US 20040204366,WO 2010036937); adrenergic agonists (US 20040101582); or opioids (WO2000003716).

Given the vital role played by NMDA receptors in a number of psychiatricand neurological disorders, they have been the subject of intensiveresearch and a multitude of antagonists/blockers/modulators have beendescribed. They can be broadly classified in three main groups as afunction of their site of action on the NMDA receptor. They thereforeinclude:

1. Competitive antagonists targeting either the glutamate binding site,for example selfotel, perzinfotel and the prodrugs (WO 2009029618) orthe glycine binding sites for example gavestinel, GV-196771 (Wallace etal., 2002, Neurology, 59, 1694-1700) and the quinolines reported inpatent application WO 2010037533. This category also includes partialagonists of the glycine sites such as D-cycloserine (US 2011160260).

2) Non-competitive (or allosteric) antagonists which act on manymodulator sites of receptor regulation, such as, for example, thepolyamine and phenylethanolamine sites. Compounds belonging to thisfamily are currently the most clinically studied. One of the topcontenders is ifenprodil (23210-56-2) and more selective derivatives ofthe latter for the NMDA receptor are currently undergoing clinicalevaluation such as, for example, traxodopril, RGH-896, MK-0657, EVT-101and EVT-103 (Mony et al., 2009, Br. J. Pharmacol., 157, 1301-1317).

3) Non-competitive antagonists, channel pore blockers. This is thefamily which has had the most success clinically because ketamine(Ketalar®, anaesthetic/analgesic), dextromethorphan (Atuxane®,antitussive), memantine (Ebixa®, anti-Alzheimer), amantadine (Mantadix®,antiviral then antiparkinsonian), felbamate (Taloxa®, anticonvulsant)are commercially available. Phencyclidine (Sernyl®) developed as ananaesthetic has been withdrawn from the market and dizocilpine (MK-801)is not commercially available as a medication.

The compounds of the invention belong to this latter family ofnon-competitive antagonists which block the NMDA receptor channels. Amajor advantage of compounds of this type resides in the fact that theydo not block the channel except when it is open; they are therefore moreeffective the more excessive the NMDA receptor activity. We can alsoeasily see that the biophysical characteristics of theblocker/antagonist, which affects the frequency and duration of channelopening, will play a critical role in its pharmacological activity andits risk/benefit ratio. Several compounds of this type have beenclinically studied such as, for example, CNS-5161 (160754-76-7),neramexane (219810-59-0), dimiracetam (126100-97-8), V-3381(1104525-45-2), NEU-2000 (640290-67-1). Others are at the pre-clinicalstage, among which we cite as examples the oxazolidines claimed inpatent application WO 2009092324, indanes (WO 2009069610),diarylethylamines (WO 2010074647), arylcyclohexylamines (WO 2010142890),ketamine and phencyclidine analogues (Zarantonello et al., 2011, Bioorg.Med. Chem. Lett., 21, 2059-2063).

The present invention concerns the derivatives represented by generalformula (1):

wherein:

-   -   X₁ represents a hydrogen atom or fluorine atom;    -   X₂ is a hydrogen atom or fluorine atom or chlorine atom;    -   R1 represents a hydrogen atom or fluorine atom or chlorine atom        or methyl group or methoxy group or cyano group;    -   R2 represents independently or together a methyl group or ethyl        group.

Preferably, the compounds of general formula (1) according to theinvention are those in which:

-   -   X₁ represents a hydrogen atom or fluorine atom;    -   X₂ is a hydrogen atom or fluorine atom or chlorine atom;    -   R1 a hydrogen atom or fluorine atom or chlorine atom or methyl        group or methoxy group or cyano group;    -   R2 is an ethyl group.

The compounds of the invention may intervene as pure diastereoisomers oras mixtures of diastereoisomers. More specifically, the inventionrelates to pure diastereoisomers in which the 1-carboxamide group andthe 3-amino group occupy opposite sides of the plane defined bycyclobutane. This stereochemical relationship between said substituentsis termed ‘trans’ in the present invention. The invention thereforerelates to pure trans diastereoisomers of the following products:

-   trans-3-amino-N,N-diethyl-1-phenylcyclobutanecarboxamide,-   trans-3-amino-N,N-dimethyl-1-phenylcyclobutanecarboxamide-   trans-3-amino-N,N-diethyl-1-(2-fluorophenyl)-cyclobutanecarboxamide,-   trans-3-amino-N,N-diethyl-1-(3-methoxyphenyl)-cyclobutanecarboxamide,-   trans-3-amino-N,N-diethyl-1-(3-fluorophenyl)-cyclobutanecarboxamide,-   trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)-cyclobutanecarboxamide,-   trans-3-amino-N,N-diethyl-1-(3-methylphenyl)-cyclobutanecarboxamide,-   trans-3-amino-N,N-diethyl-1-(3-cyanophenyl)-cyclobutanecarboxamide,-   trans-3-amino-N,N-diethyl-1-(2-fluoro-3-chlorophenyl)-cyclobutanecarboxamide,-   trans-3-amino-N,N-diethyl-1-(2,5-difluorophenyl)-cyclobutanecarboxamide,-   trans-3-amino-N,N-diethyl-1-(3,5-difluorophenyl)-cyclobutanecarboxamide,-   trans-3-amino-N,N-diethyl-1-(3,5-dichlorophenyl)-cyclobutanecarboxamide.    as well as their pharmaceutically acceptable salts.

The term “pure diastereoisomers” designates that the ‘trans’diastereoisomer of the compound of general formula (1) contains lessthan 5% of the ‘cis’ diastereoisomer, in other words the one in whichthe 1-carboxamide group and the 3-amino group occupy the same half-spaceof the plane defined by cyclobutane.

The term “diastereoisomers” designates in the context of the presentinvention stereoisomers which are not mirror images of each other.

The term “steroisomers” designates in the context of the presentinvention isomers of identical constitution but which differ in terms ofthe arrangement of their atoms in space.

The closest state of the technique is represented by the derivativesdescribed in patent application WO 2003063797 and having the followingformula:

wherein:

m and p are independently equal to 0, 1, 2 or 3;

The dotted line represents a double bond when R₁a is absent;

R1 can be a NR₆R₇ group with R₆ and R₇ possibly representing a hydrogenatom;

R₁a can be a hydrogen atom;

R2 can be an aryl group substituted or unsubstituted;

J can be a bond;

R3 can be a —C(Z₁)—R₅ group with R₅ possibly representing a NR₆aR₇agroup;

R₆a and R₇a possibly represent an alkyl group substituted orunsubstituted and Z₁ possibly represents a carbonyl group (C═O);

Rx can be one or several substituted or non-attached group(s) to all theavailable carbon atoms in the ring but also a hydrogen atom.

This patent application therefore covers a considerable number ofcompounds, the large majority of which are of the cyclobutane type (m=Oand p=1). Among the latter only four are given as examples in saidpatent. This concerns the compounds of the following formula:

wherein G is a NH₂ or N(CH₃)₂ or NH(CH₂CH₃) or NH(CH₂CHCH₂) group.

The compounds in this patent application are claimed as inhibitors ofthe current produced by type Kv1 voltage-dependent potassium channelsand in particular the current produced by isoform Kv1.5.

They are presented as useful in a broad range of indications that doesnot include the treatment of depression or pain.

It is important to mention that the compounds of the present inventiondo not interact with the potassium channels and in particular with typeKv1.5 channels. Moreover, the NMDA antagonist activity of the compoundsof the invention is found to be highly sensitive to structural changesin the compounds of formula (1). Thus the NMDA antagonist activity issuppressed when:

1) The 1-carboxamide group is reduced to a 1-aminomethyl group, such asthat of the cyclobutane compounds of patent WO 2003/063797;

2) The amino group in position 3 on cyclobutane is different from aprimary amine group (NH₂). In patent application WO 2003063797, the3-amino group is substituted by a C(G)═NCN group;

3) The “cis” stereochemistry between the 1-aryl and 3-amino groups isnot present. In fact when the 1-aryl and 3-amino groups are in “trans”stereochemistry, the corresponding compounds have no affinity for theNMDA receptor.

The state of the technique is also represented by the derivativesdescribed in patent application WO 99/52848 and corresponding to thefollowing formula:

wherein:

X is different from a hydrogen atom;

A can be an NR₇ group with R₇ different from a hydrogen atom;

R3 can be a C(O)NR₈R₁₀ group in which R₈ and R₁₀ can be C₁-C₄ alkylchains. Said compounds are claimed as being selective inhibitors of type4 phosphodiesterases, useful for treating inflammatory and autoimmunediseases. The compounds of the present invention therefore differ fromthose described in application WO 99/52848 in terms of both theirchemical structure and their pharmacological activity.

The state of the technique is also represented by the derivativesdescribed in patent application WO 2010/112597 and having the generalformula:

wherein:

a can be a single bond;

Ar represents a phenyl group substituted or unsubstituted, or apyridine-3-yl core substituted by one or more halogen atom or alkylgroups or alkoxide groups or by a cyano group;

R1 and R2 can represent independently or together a C₁-C₆ alkyl group.

Contrary to the compounds of patent application WO 2010/112597, those ofthe present invention do not have affinity for the serotonin andnoradrenalin reuptake sites. The compounds of formula (1) thereforediffer from those described in application WO 2010/112597 not only interms of their chemical structure but also in terms of theirpharmacological activity.

The state of the technique is finally represented by the compoundsdescribed in patent application WO 2000/051607 and having the generalformula:

wherein R12 and R13 represent a C₁-C₆ alkyl group or a C₂-C₆ alkenylgroup or a C₂-C₆ alkynyl group substituted or unsubstituted.

Said derivatives are chemokine modulators useful in the prevention ortreatment of certain inflammatory or immune system diseases. Here againthe compounds of the present invention thus differ from those describedin application WO 2000/051607, in terms of both their chemical structureand their pharmacological activity.

The present invention also covers salts of the derivatives of generalformula (1) with pharmaceutically acceptable organic or mineral acids.In the present invention, the term “pharmaceutically acceptable” refersto molecular entities and compositions which have no adverse or allergiceffect or any unwanted reaction when administered to humans. When usedhere, the term “pharmaceutically acceptable excipient” includes anydiluents, adjuvants or excipients, such as preservatives, fillers,disintegrating agents, wetting agents, emulsifiers, dispersing agents,antibacterial or antifungal agents, or even agents which help delayintestinal and digestive absorption and resorption. The use of thesemedia or carriers is well known to the person skilled in the art. Theterm “pharmaceutically acceptable salts” of a compound refers to thesalts defined here and which possess the pharmacological activity of theparent compound. Such salts include: acid addition salts formed withmineral acids, such as hydrochloric acid, hydrobromic acid, sulphuricacid, nitric acid, phosphoric acid and similar, or formed with organicsalts, such as acetic acid, benzensulphonic acid, benzoic acid,camphorsulphonic acid, citric acid, ethanesulphonic acid, fumaric acid,glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,hydroxynaphtoic acid, 2-hydroxyethanesulphonic acid, lactic acid, maleicacid, malic acid, mandelic acid, methanesulphonic acid, muconic acid,2-napthalenesulphonic acid, proprionic acid, salicylic acid, succinicacid, dibenzoyl-L-tartic acid, tartric acid, p-toluenesulphonic acid,trimethylacetic acid, trifluoroacetic acid and similar.

The pharmaceutically acceptable salts also include solvent (solvates)addition forms or crystalline forms (polymorphs), such as defined here,of the same acid addition salt.

The present invention also covers compounds of formula (1) as well astheir pharmaceutically acceptable salts for use as medication.

The present invention concerns compounds of formula (1) as well as theirpharmaceutically acceptable salts for use as NMDA receptor antagonists.

The present invention also concerns compounds of formula (1) as well astheir pharmaceutically acceptable salts for use as medication intendedfor the treatment and/or prevention of depression.

The present invention also concerns compounds of formula (1) as well astheir pharmaceutically acceptable salts for use as medication for thetreatment of pain, especially pain due to excessive nociception,neuropathic pain and mixed pain.

Among the types of pain potentially sensitive to the action of compoundsof general formula (1), we can cite more particularly as non-limitingexamples:

-   -   Peripheral or central neuropathic pain resulting from nerve        lesions of traumatic origin (for example stroke), metabolic        origin (for example diabetes), infectious origin (for example        HIV, shingles, herpes), trigeminal neuralgia, pain due to        chemotherapy and/or radiotherapy;    -   inflammatory pain, for example rheumatoid arthritis, septic        arthritis, osteoarthritis, polyarthritis, gout,        spondylarthritis, acute abarticular rheumatism, visceral pain,        for example irritable bowel syndrome, Crohn's disease;    -   Pain due to excessive nociception, such as posttraumatic pain,        postoperative pain, burns, twisting/distension, renal or hepatic        colic attacks, joint pain, arthritis, spondylarthropathies;    -   Mixed pain such as cancer pain, back and lower back pain or        other types of pain that are difficult to classify such as        headaches, fibromyalgia, pain associated with vascular/ischemic        problems such as angina, Reynaud's disease.

The present invention also concerns compounds of formula (1) as well astheir pharmaceutically acceptable salts for use as medication for thetreatment and/or prevention of inflammation of the joints. Among thetypes of inflammation potentially sensitive to the action of thecompounds of general formula (1), we can more particularly cite as anon-limiting examples: inflammatory monoarthritis, rheumatoid arthritis,septic arthritis, osteoarthritis rheumatoid polyarthritis, gout,spondylarthritis, acute abartricular rheumatism.

The present invention moreover concerns a pharmaceutical compositioncharacterised in that it contains at least one compound of generalformula (1) or one of its pharmaceutically acceptable salts as theactive principle.

The invention also covers a pharmaceutical composition characterised inthat it includes at least one compound of general formula (1) or one ofits pharmaceutically acceptable salts and at least one pharmaceuticallyacceptable excipient.

The invention also covers a pharmaceutical composition for use as amedication for the treatment and/or prevention of depression.

The invention further covers a pharmaceutical composition for use as amedication for the treatment of pain, particularly pain caused byexcessive nociception, and neuropathic and mixed pain.

The pharmaceutical compositions according to the present invention canbe formulated for administration to humans. These compositions areproduced such that they can be administered by oral, sublingual,subcutaneous, intramuscular, intravenous, transdermal, local or rectalroute. In this case, the active ingredient can be administered inadministration unit forms, mixed with conventional pharmaceuticalsupports, to human beings. Suitable administration unit forms includeforms by oral route such as tablets, capsules, powders, granules andoral solutions or suspensions, sublingual and buccal forms ofadministration, subcutaneous, topical, intramuscular, intravenous,intranasal or intraocular forms of administration and rectal forms ofadministration.

Advantageously, the pharmaceutical composition according to the presentinvention is formulated for administration by oral or topical route.Administration by topical route is the preferred route for the treatmentof certain types of pain, such as for example joint pain.

The term topical administration refers to local administration to theskin or mucous membrane.

Suitable formulations for the administration form chosen are known tothe person skilled in the art and are described for example in:Remington, The Science and Practice of Pharmacy, 19^(th) edition, 1995,Mack Publishing Company.

When a solid composition in the form of tablets is prepared, theprinciple active ingredient is mixed with a pharmaceutical carrier suchas gelatine, starch, lactose, magnesium stearate, talc, gum arabica,silica or similar. The tablets can be coated with saccharose or otherappropriate materials, or they can be treated such that they haveprolonged or delayed activity and release a predetermined amount ofactive principle in a continuous manner.

A capsule preparation is obtained by mixing the active ingredient with adiluent and pouring the mixture obtained into soft or hard capsules.

A preparation in the form of a syrup or elixir can contain the activeingredient along with a sweetener and an antiseptic, as well as aflavouring agent and a suitable dye.

Powders or granules that are dispersible in water can contain the activeingredient mixed with dispersing agents or wetting agents, or suspendingagents, as well as with flavour correctors or sweeteners.

For rectal administration, suppositories are used which are preparedwith binding agents that dissolve at rectal temperature, for examplecocoa butter or polyethylene glycols.

For parenteral (intravenous, intramuscular, intradermal, subcutaneous),intranasal or intraocular administration, aqueous suspensions, isotonicsaline solutions or sterile and injectable solutions are used whichcontain dispersing agents and/or pharmacologically compatible wettingagents.

The active ingredients can also be formulated as microcapsules, possiblywith one or more additive supports if necessary.

Topical administration of the pharmaceutical composition can be obtainedby application of a solution, dispersion, gel, lotion, milk, ointment,salve cream, drops or other carrier used for topical application andwell known to the person skilled in the art. One possible method is theadministration of the pharmaceutical composition by means of an aerosolspray allowing fine liquid droplets to be sprayed for distribution overthe entire surface to be treated or, to the contrary, to restrict thisprecisely to a particular zone to be treated, or in a solid form such asa stick. Another example is a patch or strip which allows continuousrelease of the topical composition. The patch can be a reservoir and aporous membrane or solid matrix well known to the person skilled in theart. Other modes of administration such as iontophoresis orelectroporation can also be used.

The compositions described in this invention can also includeingredients or compounds usually mixed with such topical preparations,for example the compositions can also include additional ingredientssuch as carriers, moisturisers, oils, fats, waxes, surfactants,thickening agents, antioxidants, viscosity stabilisers, chelatingagents, buffers, preservatives, perfumes, colorants, humectants,emollients, dispersing agents, sun creams with compounds blockingradiation and particularly UV blockers, antibacterials, antifungals,disinfectants, vitamins, antibiotics or other anti-acne agents, as wellas other adapted substances with no harmful adverse effect on theactivity of the topical composition. For example, additional ingredientscan be used such as sodium acid phosphate, witch hazel extract,glycerine, apricot kernel oil, maize oil. In addition to the compoundsdescribed above, compositions of the present invention can optionallycontain other ingredients. For example triethanolamine can be added as areticulating agent. A preservative such as butylated hydroxytoluene canalso be added. Other irritation reducing agents can also be added; inthis respect this includes but is not limited to glycerol. For topicaladministration, the compositions can contain conventional emollients andemulsifiers including alginates, glyceryl stearate, PEG-100 stearate,ketyl alcohol, propylparaben, butylparaben, sorbitols, ethoxylatedanhydrosorbitol monostearate (TWEEN), white petrolatum (Vaseline),triethaolamine, emu oil, aloe vera, lanolin, cocoa butter and otherextracts.

The compositions described can be applied to the patient's skin area tobe treated. The frequency of application will depend on circumstancesand the patient. For example the compositions can be applied daily,twice a day or even more frequently.

The doses of a compound of general formula (1) or one of itspharmaceutically acceptable salts in the composition of the inventioncan be adjusted in order to obtain a quantity of substance that iseffective in achieving the desired therapeutic response for acomposition specific to the administration method. The effective dose ofthe compound of the invention varies as a function of numerousparameters such as, for example, the administration route chosen,weight, age, sex, type of disease, sensitivity of the individual to betreated. Consequently the optimum dosage can be established by thespecialists in the field as a function of parameters the specialistconsiders to be relevant. Although the effective doses can vary withinbroad proportions, the daily doses can be scaled between 1 mg and 1000mg per 24 h for an adult of average weight of 70 kg, in one or moredivided doses.

Finally the invention includes the method for synthesis of products ofthe compounds of general formula (1) as well as those of synthesisintermediates of formula (C) and (D).

The compounds of general formula (1) can be obtained by the processdescribed in the reaction diagram hereafter.

The preparation of the compounds of the invention uses as startingmaterial derivatives of benzeneacetic acid of formula (A) that arecommercially available such as: benzeneacetic acid (RN 103-82-2);2-fluorobenzene-acetic acid (RN 451-82-1); 3-fluorobenzeneacetic acid(RN 331-25-9); 3-chlorobenzeneacetic acid (RN 1878-65-5);3-methylbenzeneacetic acid (RN 621-36-3); 3-cyanobenzeneacetic acid (RN1878-71-3); 3-methoxybenzeneacetic acid (RN 1798-09-0);2,5-difluorobenzeneacetic acid (RN 85068-27-5);3,5-difluorobenzeneacetic acid (RN 105184-38-1);3,5-dichlorobenzeneacetic acid (RN 51719-65-4);2-fluoro-3-chlorobenzeneacetic acid (RN 261762-96-3). The derivatives offormula (A) are condensed with epichlorhydrin according to a methodadapted from that described in patent application WO 2007/038452 to givederivatives of formula (B) in which the alcohol and carboxylic acidgroups show ‘cis’ stereochemistry. Said patent does not describe theintermediates of formula (B). The lactones of formula (C) are thenformed from derivatives of formula (B) by using a conventional method ofactivation of the acid group, for example such as using an alkylchloroformiate as described in application WO 2008/092955. Opening ofthe lactone of formula (C) is then advantageously carried out using themagnesium salt of the appropriate secondary amine according to Williamset al. (Tetrahedron Lett., 1995, 36, 5461-5464) to produce thecorresponding carboxamide of formula (D). Introduction of the primaryamine group in position 3 of cyclobutane with inversion of thestereochemistry can be achieved through the intermediate of the azide offormula (E) according to Soltani Rad et al. (Tetrahedron Lett., 2007,48, 3445-3449). Reduction of the azido group to the correspondingprimary amine is then achieved either by catalytic hydrogenation or by aStaudinger reaction. Alternatively conversion of the compound of formula(D) into the amine of formula (1) can be carried out through theintermediate of phthalimide of formula (F) according to Gabriel'sconventional method (for example application WO 2006081179).

The following examples illustrate the invention without being limiting.In the examples below:

(i) different crystalline shapes can give rise to different meltingpoints; the melting points reported in this application are those of theproducts prepared according to the methods described and are notcorrected;

(ii) the structure of the products obtained according to the inventionis confirmed by the nuclear magnetic resonance (NMR) spectra and by massspectrometry; the purity of the final product is verified by TLC andcentesimal analysis;

(iii) the NMR spectra are recorded in the solvent given: chemical shifts(δ) are expressed in parts per million (ppm) relative totetramethylsilane; the multiplicity of signals is indicated by: s,singulet; d, doublet; t, triplet; q, quadruplet; qu, quintuplet, m,multiplet; 1, large;

(iv) the different symbols for units have their usual meaning: μg(microgram); mg (milligram); g (gram); mL (millilitre); mV (millivolt);° C. (degrees Celsius); mmol (millimole; nmol (nanomol); cm(centimetre); nm (nanometre); min (minute); ms (millisecond), Hz(hertz);

(v) the abbreviations have the following meaning: Mp (melting point); Bp(boiling point);

(vi) the term “ambient temperature”, refers to a temperature between 20°C. and 25° C.

EXAMPLE 1 trans-3-amino-N,N-diethyl-1-phenylcyclobutanecarboxamide (1a1)Step 1: cis-1-phenyl-3-hydroxy-cyclobutanecarboxylic acid (B1)

Place 2.2 eq of isopropylmagnesium chloride in a three-necked flask andcool the reaction medium to 0° C. Add 1 eq of phenylacetic acid dilutedin THF; the temperature must be kept between 40 and 50° C. Cool themedium to 20° C. and add 1.8 eq of epichlorhydrin; the temperature mustbe kept between 20 and 25° C., and stir at this temperature for 45 min.Next, add 2 eq of isopropylmagnesium chloride (2M in THF) dropwise andstir at room temperature for 2 h. Next heat the reaction medium to 60°C. for 19 h. Allow the medium to cool then acidify with an HCl solution(1N) to pH 1. Add dichloromethane (DCM) and extract. Decant, dry theorganic phase over MgSO₄, then evaporate the DCM under reduced pressure.Purify the residue by flash chromatography with the following eluent:DCM, then DCM/methanol 70:30. The title product is obtained in the formof a pale yellow solid (yield=70%).

C₁₁H₁₂O₃ (molecular weight=192).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.50 (m, 2H), 2.74 (t, 2H, J=9.4 Hz),3.32 (s, 1H), 3.85 (qu, 1H, J=7.2 Hz), 7.22-7.38 (m, 5H), 12.21 (s, 1H).

SM-ESI: 193.1 (MH⁺).

Step 2: 4-phenyl-2-oxabicyclo[2.1.1]hexane-3-one (C1)

Place 1 eq of compound B1) in a flask, dilute in THF and 1.03 eq oftriethylamine. Stir at room temperature until dissolved then cool thereaction medium to 0° C. Add 1 eq of ethyl chloroformiate and stir atthis temperature for 1 h then bring back to room temperature and stirfor 20 h. Evaporate THF under reduced pressure, take up the residue withethyl acetate (AcOEt). Decant, dry the acetate on MgSO₄, then evaporateunder reduced pressure. Purify the residue by flash chromatography withthe following eluant: heptane, then heptane/AcOEt 60:40. The titleproduct is obtained in the form of a colourless oil (yield=87%).

C₁₁H₁₀O₂ (MW=174).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 2.71 (m, 2H), 2.89 (m, 2H), 4.97 (s,1H), 7.31-7.42 (m, 5H).

SM-ESI: 175 (MH⁺).

Step 3: cis-3-hydroxy-N,N-diethyl-1-phenylcyclobutanecarboxamide (D1a)

Place 1 eq of compound (C1), 2 eq of diethylamine and THF in athree-necked flask. Cool the reaction medium to −20° C., then add 3 eqof isopropylmagnesium chloride dropwise (2M in THF) keeping thetemperature below −5° C. Stir the mixture for 2 h at a temperaturebetween −10 and −20° C. Hydrolyze the reaction medium with a saturatedNaCl solution then add an HCl solution (1N) and extract with AcOEt. Drythe organic phase over MgSO₄, filter and concentrate. Purify the residueby flash chromatography with the following mixture as the eluant:DCM/methanol 85:15. The title product is obtained in the form a paleyellow solid (yield=99%).

C₁₅H₂₁NO₂ (MW=247).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.63 (t, 3H, J=7.2 Hz), 1.08 (t, 3H,J=7.2 Hz), 2.72 (m, 2H), 2.82 (m, 2H), 2.90 (q, 2H, J=7.2 Hz), 3.21 (q,2H, J=7.2 Hz), 4.36 (qu, 1H, J=7.4 Hz), 7.21-7.36 (m, 5H). The signalcorresponding to the H in OH is not visible on the spectrum.

SM-ESI: 248 (MH⁺).

Step 4: trans-3-azido-N,N-diethyl-1-phenylcyclobutanecarboxamide (E1a)

Place 1 eq of compound (D1a), 1.5 eq of N-(p-toluenesulfonyl)imidazole,2 eq of triethylamine, 0.025 eq of tetrabutylammonium iodide, 3 eq ofsodium azide and DMF in a flask. Stir and heat the reaction medium at160° C. for 4 h. Pour the reaction medium onto ice water and extractwith ethyl ether. Dry the organic phase over MgSO₄, filter andconcentrate. Purify the residue by flash chromatography with thefollowing mixture as the eluant: heptane/AcOEt 70:30. The title productis obtained in the form of a colourless oil (yield=65%).

C₁₅H₂₀N₄O (MW=272).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.52 (t, 3H, J=7.2 Hz), 1.11 (t, 3H,J=7.2 Hz), 2.47 (m, 2H), 2.89 (q, 2H, J=7.2 Hz), 3.14 (m, 2H), 3.34 (q,2H, J=7.2 Hz), 3.96 (qu, 1H, J=7.8 Hz), 7.23 (m, 3H), 7.35 (m, 2H).

SM-ESI: 273 (M+H⁺).

Step 5: trans-3-amino-N,N-diethyl-1-phenylcyclobutanecarboxamide (1a1)

Dissolve 1 eq of compound (E1a) in methanol in a flask. Degas thesolution for 30 min with nitrogen then add Pd/C (20% weight). Purge thesystem (cycle: vacuum/H₂ gas) and hydrogenate the reaction medium for 3h at room temperature with stirring. Filter the catalyst and evaporatethe solvent. Purify the residue by flash chromatography with thefollowing mixture as the eluant: DCM/methanol/NH₄OH: 90:9:1. The titleproduct is obtained in the form of a colourless oil (yield=70%).

C₁₅H₂₂N₂O (MW=246).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.50 (t, 3H, J=7.2 Hz), 1.10 (t, 3H,J=7.2 Hz), 2.11 (m, 2H), 2.92 (q, 2H, J=6.8 Hz), 3.12 (m, 2H), 3.32 (q,2H, J=6.8 Hz), 3.46 (qu, 1H, J=8.0 Hz), 7.18-7.35 (m, 5H). The signalcorresponding to the H in NH₂ is not visible on the spectrum.

SM-ESI: 247 (MH⁺).

Maleate of the Title Compound

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 185° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.42 (t, 3H, J=7.0 Hz), 1.02 (t, 3H,J=7.0 Hz), 2.56 (m, 2H), 2.85-2.96 (m, 4H), 3.25 (q, 2H, J=6.8 Hz), 3.54(qu, 1H, J=8.4 Hz), 6.03 (s, 2H), 7.26 (m, 3H), 7.39 (t, 2H, J=7.6 Hz),8.00 (s, 2H). The signal corresponding to the H in NH2 is not visible onthe spectrum.

¹³C-NMR (DMSO d₆, 100 MHz) δ (ppm): 12.02, 12.15, 36.93, 39.19, 40.07,41.19, 46.61, 124.87, 126.51, 128.71, 136.02, 142.69, 167.19, 171.10.

% Theoretical: C, 62.97; H, 7.23; N, 7.73.

% Found: C, 63.00; H, 7.17; N, 7.78.

EXAMPLE 2 trans-3-amino-N,N-dimethyl-1-phenylcyclobutanecarboxamide(1a2) Step 3: cis-3-hydroxy-N,N-dimethyl-1-phenylcyclobutanecarboxamide(D1b)

Identical to step 3 described in Example 1, using dimethylamine insteadof diethylamine. The title product is obtained in the form of acolourless oil (yield=89%).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 2.65 (m, 2H), 2.55 (s, 3H), 2.95 (s,3H), 2.80 (m, 2H), 4.27 (qu, 1H, J=7.8 Hz), 7.19-7.35 (m, 5H). Thesignal corresponding to the H in OH is not visible on the spectrum.

Step 4: trans-3-azido-N,N-dimethyl-1-phenylcyclobutanecarboxamide (E1b)

Identical to step 4 described in Example 1. The title product isobtained in the form of a beige solid (yield=95%).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 2.50 (m, 2H), 2.54 (s, 3H), 2.96 (s,3H), 3.18 (m, 2H), 3.97 (qu, 1H, J=7.8 Hz), 7.24 (m, 3H), 7.36 (m, 2H).

Step 5: trans-3-amino-N,N-dimethyl-1-phenylcyclobutanecarboxamide (1a2)

Identical to step 5 described in Example 1. The title product isobtained in the form of a colourless oil (yield=84%).

C₁₃H₁₈N₂O (MW=218).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 2.13 (m, 2H), 2.55 (s, 3H), 2.95 (s,3H), 3.15 (m, 2H), 3.47 (qu, 1H, J=7.8 Hz), 7.19-7.35 (m, 5H). Thesignal corresponding to the H in NH₂ is not visible on the spectrum.

SM-ESI: 219 (MH⁺).

Maleate of the Title Compound

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 163° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.51 (m, 5H), 2.86 (s, 3H), 2.98 (m,2H), 3.36 (s, 1H), 3.53 (qu, 1H, J=8.4 Hz), 6.03 (s, 2H), 7.26 (m, 3H),7.39 (t, 2H, J=7.6 Hz), 8.05 (s, 3H).

¹³C-NMR (DMSO d₆, 100 MHz) δ (ppm): 35.80, 37.20, 37.34, 39.91, 46.54,124.94, 126.59, 128.72, 136.00, 142.43, 167.15, 171.68.

% Theoretical: C, 61.07; H, 6.63; N, 8.38.

% Found: C, 60.73; H, 6.43; N, 8.15.

EXAMPLE 3trans-3-amino-N,N-diethyl-1-(2-fluorophenyl)-cyclobutanecarboxamide (1b)Step 1: cis-3-hydroxy-1-(2-fluorophenyl)-cyclobutanecarboxylic acid (B2)

Identical to step 1 described in 1, by using 2-fluorophenylacetic acidas the starting product. The title product is obtained in the form of awhite solid (yield=49%).

C₁₁H₁₁FO₃ (MW=210).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 2.80 (m, 2H), 2.97 (m, 2H), 4.29 (qu,1H, J=6.4 Hz), 7.04-7.23 (m, 4H). The signals corresponding to the H inOH in the alcohol and acid are not visible on the spectrum.

SM-ESI: 211 (MH⁺).

Step 2: 4-(2-fluorophenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C2)

Identical to step 2 described in Example 1. The title product isobtained in the form of a colourless oil (yield=81%).

C₁₁H₉FO₂ (MW=192).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 2.75 (m, 2H), 2.99 (m, 2H), 5.01 (s,1H), 7.07-7.42 (m, 4H).

SM-ESI: =193 (MH⁺).

Step 3:cis-3-hydroxy-N,N-diethyl-1-(2-fluorophenyl)-cyclobutanecarboxamide(D2a)

Identical to step 3 of Example 1. The title product is obtained in theform of a white solid (yield=85%).

C₁₅H₂₀NO₂F (MW=265).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.47 (t, 3H, J=6.8 Hz), 1.10 (t, 3H,J=6.8 Hz), 2.77-2.89 (m, 4H), 2.95 (m, 2H), 3.31 (m, 2H), 4.32 (qu, 1H,J=6.8 Hz), 7.04 (t, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.8 Hz), 7.26 (m, 1H),7.37 (t, 1H, J=7.8 Hz). The signal corresponding to the H in OH is notvisible on the spectrum.

SM-ESI: 266 (MH⁺).

Step 4:trans-3-azido-N,N-diethyl-1-(2-fluorophenyl)-cyclobutanecarboxamide(E2a)

Identical to step 4 described in 1. The title product is obtained in theform of a colourless oil (yield=75%).

C₁₅H₁₉N₄OF (MW=290).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.42 (t, 3H, J=7.0 Hz), 1.10 (t; 3H,J=7.0 Hz), 2.55 (m, 2H), 2.98 (q, 2H, J=7.0 Hz), 3.19 (m, 2H), 3.31 (q,2H, J=7.0 Hz), 4.02 (qu, 1H, J=8.0 Hz), 7.03 (m, 1H), 7.14-7.29 (m, 3H).

SM-ESI: 291 (MH⁺).

Step 5:trans-3-amino-N,N-diethyl-1-(2-fluorophenyl)-cyclobutanecarboxamide (1b)

Identical to step 5 described in example 1. The title product obtainedis in the form of a colourless oil (yield=90%).

C₁₅H₂₁N₂OF (MW=264).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.42 (t, 3H, J=6.8 Hz), 1.10 (t, 3H,J=6.8 Hz), 2.19 (m, 2H), 3.00 (q, 2H, J=6.8 Hz), 3.17 (m, 2H), 3.31 (q,2H, J=6.8 Hz), 3.53 (qu, 1H, J=8.0 Hz), 7.00 (m, 1H), 7.11-7.31 (m, 3H).The signal corresponding to the H in NH₂ is not visible on the spectrum.

SM-ESI: 265 (MH⁺).

Maleate of the Title Compound.

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 193° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.01 (t, 3H, J=6.8 Hz), 0.77 (t, 3H,J=6.8 Hz), 2.36 (m, 2H), 2.72 (m, 4H), 2.97 (q, 2H, J=6.8 Hz), 3.22 (s,1H), 3.38 (qu, 1H, J=8.0 Hz), 5.81 (s, 2H), 6.94 (m, 1H), 7.04-7.14 (m,2H), 7.33 (m, 1H), 7.75 (s, 3H).

¹³C-NMR (DMSO d₆, 100 MHz) δ (ppm): 12.00, 12.20, 36.14, 39.97, 40.60,41.19, 43.60, 115.71 (d, ²J_(C-F)=21 Hz), 124.64 (d, ⁴J_(C-F)=4 Hz),128.00 (d, ³J_(C-F)=5 Hz), 128.80 (d, =8 Hz), 130.07 (d, ²J_(C-F)=13Hz), 136.04, 158.52, 160.96, 167.14, 169.93.

% Theoretical: C, 59.99; H, 6.62; N, 7.36.

% Found: C, 60.15; H, 6.48; N, 7.20.

EXAMPLE 4trans-3-amino-N,N-diethyl-1-(3-fluorophenyl)-cyclobutanecarboxamide (1c)Step 1: cis-3-hydroxy-1-(3-fluorophenyl)-cyclobutanecarboxylic acid (B3)

Identical to step 1 of Example 1 by using 3-fluorophenylacetic acid asthe starting acid. The title product is obtained in the form of a whitesolid (yield=52%).

C₁₁H₁₁FO₃ (MW=210).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.50 (m, 2H), 2.75 (m, 2H), 3.86 (qu,1H, J=7.2 Hz), 5.18 (s, 1H), 7.07-7.21 (m, 3H), 7.40 (m, 1H), 12.40 (s,1H).

SM-ESI: 211 (MH⁺).

Step 2: 4-(3-fluorophenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C3)

Identical to step 2 described in Example 1. The title product isobtained in the form of a colourless oil (yield=91%).

C₁₁H₉O₂F (MW=192).

¹H-NMR (DMSO d₅, 400 MHz) δ (ppm): 2.83 (s, 4H), 5.09 (s, 1H), 7.15-7.22(m, 3H), 7.38-7.47 (m, 1H).

SM-ESI: 193 (MH⁺).

Step 3:cis-3-hydroxy-N,N-diethyl-1-(3-fluorophenyl)-cyclobutanecarboxamide(D3a)

Identical to step 3 of Example 1. The title product is obtained in theform of a white solid (yield=92%).

C₁₅H₂₀NO₂F (MW=265).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.62 (t, 3H, J=7.2 Hz), 0.97 (t, 3H,J=7.2 Hz), 2.50 (m, 2H), 2.66 (m, 2H), 2.86 (q, 2H, J=7.2 Hz), 3.19 (q,2H, J=7.2 Hz), 4.05 (m, 1H), 5.12 (d, 1H, J=6.8 Hz), 7.04-7.15 (m, 3H),7.39 (m, 1H).

SM-ESI: 266 (MH⁺).

Step 4:trans-3-azido-N,N-diethyl-1-(3-fluorophenyl)-cyclobutanecarboxamide(E3a)

Identical to step 4 described in 1. The title product is obtained in theform of a colourless oil (yield=72%). ¹H-NMR (DMSO d₆, 400 MHz) δ (ppm):0.59 (t, 3H, J=7.2 Hz), 1.00 (t, 3H, J=7.2 Hz), 2.40 (m, 2H), 2.86 (q,2H, J=7.2 Hz), 3.04 (m, 2H), 3.24 (q, 2H, J=7.2 Hz), 4.07 (m, 1H),7.04-7.15 (m, 3H), 7.39 (m, 1H).

Step 5:trans-3-amino-N,N-diethyl-1-(3-fluorophenyl)-cyclobutanecarboxamide (1c)

Identical to step 5 described in Example 1. The title product isobtained in the form of a colourless oil (yield=93%).

C₁₅H₂₁N₂OF (MW=264).

SM-ESI: 265 (MH⁺).

Maleate of the Title Compound

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 174° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.49 (t, 3H, J=7.0 Hz), 1.02 (t, 3H,J=7.0 Hz), 2.56 (m, 2H), 2.91 (m, 4H), 3.26 (q, 2H, J=7.0 Hz), 3.35 (s,1H), 3.53 (qu, 1H, J=8.4 Hz), 6.03 (s, 2H), 7.01 (d, 1H, J=8.0 Hz),7.09-7.20 (m, 2H), 7.42 (m, 1H), 7.99 (s, 3H).

¹³C-NMR (DMSO d₆, 100 MHz) δ (ppm): 12.10, 36.93, 39.23, 39.91, 41.18,46.40, 111.03 (d, ²J_(C-F)=22 Hz), 113.39 (d, ²J_(C-F)=21 Hz), 121.11(d, ⁴J_(C-F)=2 Hz), 130.77 (d, ³J_(C-F)=9 Hz), 136.02, 145.55 (d, 7 Hz),161.21, 163.64, 167.14, 170.60.

% Theoretical: C, 59.99; H, 6.62; N, 7.36.

% Found: C, 59.11; H, 6.40; N, 7.07.

EXAMPLE 5trans-3-amino-N,N-diethyl-1-(3-methoxyphenyl)-cyclobutanecarboxamide(1d) Step 1: cis-3-hydroxy-1-(3-methoxyphenyl)-cyclobutanecarboxylicacid (B4)

Identical to step 1 of Example 1 by using 3-methoxyphenylacetic insteadof phenylacetic acid. The title product is obtained in the form of awhite solid (yield=50%).

C₁₂H₁₄O₄ (MW=222)

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.50 (m, 2H), 2.73 (m, 2H), 3.75 (s,3H), 3.86 (qu, 1H, J=7.2 Hz), 5.14 (s, 1H), 6.82 (dd, 1H, J=8.0 Hz andJ=2.0 Hz), 6.87 (s, 1H), 6.93 (d, 1H, J=8.0 Hz), 7.26 (t, 1H, J=8.0 Hz),12.23 (s, 1H).

SM-ESI: 222.

Step 2: 4-(3-methoxyphenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C4)

Identical to step 2 described in Example 1. The title product isobtained in the form of a colourless oil (yield=85%).

C₁₂H₁₂O₂ (MW=188).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.80 (m, 4H), 3.76 (s, 3H), 5.06 (s,1H), 6.87-6.91 (m, 3H), 7.30 (t, 1H, J=8.0 Hz).

SM-ESI: 189 (MH⁺).

Step 3:cis-3-hydroxy-N,N-diethyl-1-(3-methoxyphenyl)-cyclobutanecarboxamide(D4a)

Identical to step 3 described for Example 1. The title product isobtained in the form of a white solid (yield=92%).

C₁₆H₂₃NO₃ (MW=277)

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.62 (t, 3H, J=6.8 Hz), 0.97 (t, 3H,J=6.8 Hz), 2.50 (m, 2H), 2.64 (m, 2H), 2.86 (q, 2H, J=6.8 Hz), 3.19 (q,2H, J=6.8 Hz), 3.73 (s, 3H), 4.06 (se, 1H, J=7.6 Hz), 5.08 (d, 1H, J=7.2Hz), 6.81 (m, 2H), 6.89 (d, 1H, J=7.6 Hz), 7.27 (m, 1H).

SM-ESI: 278 (MH⁺).

Step 4:trans-3-azido-N,N-diethyl-1-(3-methoxyphenyl)-cyclobutanecarboxamide(E4a)

Identical to step 4 described for Example 1. The title product isobtained in the form of a colourless oil (yield=82%).

C₁₆H₂₂N₄O₂ (MW=302).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.59 (t, 3H, J=6.8 Hz), 1.00 (t, 3H,J=6.8 Hz), 2.40 (m, 2H), 2.86 (q, 2H, J=6.8 Hz), 3.05 (m, 2H), 3.24 (q,2H, J=6.8 Hz), 3.74 (s, 3H), 3.95 (qu, 1H, J=7.6 Hz), 6.76 (m, 1H), 6.83(m, 2H), 7.30 (m, 1H).

SM-ESI: 303 (MH⁺).

Step 5:trans-3-amino-N,N-diethyl-1-(3-methoxyphenyl)-cyclobutanecarboxamide(1d)

Identical to step 5 described for Example 1. The title product isobtained in the form of a colourless oil (yield=88%).

C₁₆H₂₄N₂O₂ (MW=276).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.50 (t, 3H, J=7.0 Hz), 1.00 (t, 3H,J=7.0 Hz), 2.02 (m, 2H), 2.83 (m, 4H), 3.10 (qu, 1H, J=8.0 Hz), 3.23 (q,2H, J=7.2 Hz), 3.33 (s, 2H), 3.73 (s, 3H), 6.73-6.79 (m, 3H), 7.25 (t,1H, J=8.0 Hz).

SM-ESI: 277 (MH⁺).

Maleate of the Title Compound

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 156° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.47 (t, 3H, J=6.8 Hz), 1.02 (t, 3H,J=6.8 Hz), 2.55 (m, 2H), 2.89 (m, 4H), 3.26 (q, 2H, J=6.8 Hz), 3.35 (s,1H), 3.52 (qu, 1H, J=8.4 Hz), 3.75 (s, 3H), 6.03 (s, 2H), 6.78-6.86 (m,3H), 7.31 (t, 1H, J=8.0 Hz), 7.98 (s, 3H).

¹³C-NMR (DMSO d₆, 100 MHz) δ (ppm): 12.11, 36.98, 39.23, 39.99, 41.23,46.57, 55.03, 111.05, 111.54, 117.12, 129.89, 136.03, 144.22, 159.54,167.12, 171.02.

% Theoretical: C, 61.21; H, 7.19; N, 7.14.

% Found: C, 61.38; H, 7.09; N, 6.98.

EXAMPLE 6trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)-cyclobutanecarboxamide (1e)Step 1: cis-3-hydroxy-1-(3-chlorophenyl)-cyclobutanecarboxylic acid (B5)

Identical to step 1 described in 1 by using 3-chlorophenylacetic acid asthe starting acid. The title compound is obtained in the form of a whitesolid (yield=52%).

C₁₁H₁₁O₃Cl (MW=226.5).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.50 (m, 2H), 2.75 (m, 2H), 3.86 (qu,1H, J=7.2 Hz), 5.19 (s, 1H), 7.31-7.40 (m, 4H), 12.44 (s, 1H).

Step 2: 4-(3-chlorophenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C5)

Identical to step 2 described in Example 1. The title product isobtained in the form of a colourless oil (yield=78%).

C₁₁H₉O₂Cl (MW=208).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.84 (m, 4H), 5.09 (s, 1H), 7.29-7.45(m, 4H).

SM-ESI: 209 (MH⁺).

Step 3:cis-3-hydroxy-N,N-diethyl-1-(3-chlorophenyl)-cyclobutanecarboxamide(D5a)

Identical to step 3 described in example 1. The title compound isobtained in the form of a white solid (yield=99%).

C₁₅H₂₀NO₂Cl (MW=281.5).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.63 (t, 3H, J=6.8 Hz), 0.96 (t, 3H,J=6.8 Hz), 2.51 (m, 2H), 2.66 (m, 2H), 2.86 (q, 2H, J=6.8 Hz), 3.19 (q,2H, J=6.8 Hz), 4.05 (qu, 1H, J=7.6 Hz), 5.13 (s, 1H), 7.29-7.41 (m, 4H).

SM-ESI: 282.1 (MH⁺).

Step 4:trans-3-(dioxoisoindoline-2-yl)-N,N-diethyl-1-(3-chlorophenyl)-cyclobutanecarboxamide(F5a)

In a flask under an atmosphere of nitrogen, add 1 eq of compound (D5a),1.1 eq of triphenylphosphine, 1.05 eq of phthalimide and THF. Next, add1.2 eq of diisopropyldiazodicarboxylate (DIAD) dropwise and stir at roomtemperature for 16 h. Add water and extract with DCM. Dry the organicphase over Na₂SO₄, filter and concentrate. Purify the residue by flashchromatography with the following mixture as the eluent: heptane/AcOEt:80:20. The title product is obtained with a yield de 77%.

C₂₃H₂₃N₂O₃Cl (MW=410.5).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.67 (t, 3H, J=7.2 Hz), 1.18 (t, 3H,J=7.2 Hz), 2.91 (q, 2H, J=7.2 Hz), 3.11 (m, 2H), 3.35 (m, 2H), 3.42 (q,2H, J=7.2 Hz), 4.79 (qu, 1H, J=8.8 Hz), 7.23 (m, 1H), 7.32 (m, 2H), 7.41(s, 1H), 7.73 (m, 2H), 7.83 (m, 2H).

SM-ESI: 411.1 (MH⁺).

Step 5:trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)-cyclobutanecarboxamide (1e)

Place derivative (F5a) in solution in ethanolamine in a flask. Heat thereaction medium at 60° C. for 1 h 30. Add a mixture of ice and water,stir for 15 min and extract with AcOEt. Wash the organic phase withsaturated NaCl solution and decant. Dry the organic phase over MgSO₄,filter and concentrate. Purify the residue by flash chromatography withthe following mixture as the eluent: DCM/methanol/NH₄OH: 90:9:1. Thetitle product is obtained with a yield de 40%.

C₁₅H₂₁N₂OCl (MW=280.5).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.58 (t, 3H, J=7.2 Hz), 1.10 (t, 3H,J=7.2 Hz), 2.08 (m, 2H), 2.91 (q, 2H, J 7.2 Hz), 3.11 (m, 2H), 3.34 (q,2H, J=7.2 Hz), 3.46 (qu, 1H, J=8.0 Hz), 7.12 (dd, 1H, J=7.6 Hz and J=1.2Hz), 7.19 (m, 2H), 7.26 (m, 1H). The signal corresponding to the H inNH₂ is not visible on the spectrum.

SM-ESI: 281.1 (MH⁺).

Maleate of the Title Compound

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 167° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.50 (t, 3H, J=6.8 Hz), 1.02 (t, 3H,J=6.8 Hz), 2.56 (m, 2H), 2.86-2.95 (m, 4H), 3.26 (m, 2H), 3.34 (s, 1H),3.54 (qu, 1H, J=8.0 Hz), 6.03 (s, 2H), 7.15 (d, 1H, J=7.6 Hz), 7.34-7.44(m, 3H), 8.00 (s, 3H).

¹³C-NMR (DMSO d₆. 100 MHz) δ (ppm): 12.09, 12.12, 36.88, 39.19, 39.90,41.14, 46.37, 123.76, 124.94, 126.61, 130.65, 133.51, 136.00, 145.09,167.14, 170.54.

% Theoretical: C, 57.50; H, 6.35; N, 7.06.

% Found: C, 57.36; H, 6.26; N, 6.68.

EXAMPLE 7trans-3-amino-N,N-diethyl-1-(3-methylphenyl)-cyclobutanecarboxamide (1f)Step 1: cis-3-hydroxy-1-(3-methylphenyl)-cyclobutanecarboxylic acid (B6)

Identical to step 1 of Example 1 by using 3-methylphenylacetic acidinstead of phenylacetic acid. The title product is obtained in the formof a white solid (yield=40%).

C₁₂H₁₄O₃ (MW=206).

¹H-NMR (CDCl₃. 400 MHz) δ (ppm): 2.35 (s, 3H), 2.73 (m, 2H), 2.94 (m,2H), 4.21 (qu, 1H, J=6.4 Hz), 7.08 (d, 1H, J=7.6 Hz), 7.16 (s, 2H), 7.24(m, 1H). The signals corresponding to the H in OH in the alcohol andacid are not visible on the spectrum.

SM-ESI: 205.

Step 2: 4-(3-methylphenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C6)

Identical to step 2 described in Example 1. The title product isobtained in the form of a colourless oil (yield=74%).

C₁₂H₁₂O₂ (MW=188).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.37 (s, 3H), 2.70 (m, 2H), 2.87 (m,2H), 4.96 (s, 1H), 7.09-7.30 (m, 4H).

SM-ESI: 189 (MH⁺).

Step 3:cis-3-hydroxy-N,N-diethyl-1-(3-methylphenyl)-cyclobutanecarboxamide(D6a)

Identical to step 3 described in example 1. The title product isobtained with a yield de 77%.

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.65 (t, 3H, J=7.2 Hz), 1.08 (t, 3H,J=7.2 Hz), 2.69 (s, 3H), 2.73 (m, 2H), 2.81 (m, 2H), 2.90 (q, 2H, J=7.2Hz), 3.31 (q, 2H, J=7.2 Hz), 4.35 (qu, 1H, J=7.4 Hz), 7.04 (m, 1H), 7.11(m, 2H), 7.23 (m, 1H). The signal corresponding to the H in OH is notvisible on the spectrum.

Step 4:trans-3-azido-N,N-diethyl-1-(3-methylphenyl)-cyclobutanecarboxamide(E6a)

Identical to step 4 described in 1. The title product is obtained with ayield de 70%.

¹H-NMR (CDCl₃. 400 MHz) δ (ppm): 0.54 (t, 3H, J=7.2 Hz), 1.11 (t, 3H,J=7.2 Hz), 2.34 (s, 3H), 2.47 (m, 2H), 2.89 (q, 2H, J=7.2 Hz), 3.12 (m,2H), 3.34 (q, 2H, J=7.2 Hz), 3.95 (qu, 1H, J=7.8 Hz), 7.04 (m, 3H), 7.23(m, 1H).

Step 5:trans-3-amino-N,N-diethyl-1-(3-methylphenyl)-cyclobutanecarboxamide (1f)

Identical to step 5 described in Example 1. The title product isobtained with a yield de 57%.

C₁₆H₂₄N₂O (MW=260).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.52 (t, 3H, J=7, 2 Hz), 1.10 (t, 3H,J=7, 2 Hz), 2.11 (m, 2H), 2.33 (s, 3H), 2.92 (q, 2H, J=7.2 Hz), 3.10 (m,2H), 3.33 (q, 2H, J=7.2 Hz), 3.44 (qu, 1H, J=8.0 Hz), 7.03 (m, 3H), 7.21(m, 1H). The signal corresponding to the H in NH₂ is not visible on thespectrum.

SM-ESI: 261 (MH⁺).

Maleate of the Title Compound

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 173° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.45 (t, 3H, J=6.8 Hz), 1.02 (t, 3H,J=6.8 Hz), 2.31 (s, 3H), 2.52 (m, 2H), 2.89 (m, 4H), 3.25 (q, 2H, J=6.8Hz), 3.52 (qu, 1H, J=8.4 Hz), 6.02 (s, 2H), 7.05 (m, 3H), 7.27 (t, 1H,J=7.6 Hz), 8.00 (s, 2H). The signal corresponding to the H in NH2 is notvisible on the spectrum.

¹³C-NMR (DMSO d₆, 100 MHz) δ (ppm): 12.07, 12.13, 21.05, 36.97, 39.15,40.09, 41.18, 46.56, 48.53, 121.99, 125.43, 127.15, 128.63, 136.07,137.88, 142.66, 167.21, 171.19.

% Theoretical: C, 63.81; H, 7.50; N, 7.44.

% Found: C, 63.93; H, 7.45; N, 7.27.

EXAMPLE 8trans-3-amino-N,N-diethyl-1-(2-fluoro-3-chlorophenyl)-cyclobutanecarboxamide(1g) Step 1:cis-3-hydroxy-1-(2-fluoro-3-chlorophenyl)-cyclobutanecarboxylic acid(B7)

Identical to step 1 of Example 1 by using 2-fluoro-3-chlorophenylaceticacid instead of phenylacetic acid. The title product is obtained in theform of a white solid (yield=30%).

C₁₁H₁₀FClO₃ (MW=244.5).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.58 (m, 2H), 2.75 (m, 2H), 3.93 (qu,1H, J=7.6 Hz), 5.33 (s, 1H), 7.22 (m, 1H), 7.52 (m, 2H), 12.56 (m, 1H).

SM-ESI: 243.0.

Step 2: 4-(2-fluoro-3-chlorophenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C7)

Identical to step 2 described in Example 1. The title product isobtained in the form of a colourless oil (yield=66%).

C₁₁H₈O₂ClF (MW=226.5).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.89 (s, 4H), 5.16 (s, 1H), 7.22-7.29(m, 2H), 7.61 (m, 1H).

SM-ESI: 227 (MH⁺).

Step 3:cis-3-hydroxy-N,N-diethyl-1-(2-fluoro-3-chlorophenyl)-cyclobutanecarboxamide(D7a)

Identical to step 3 described in example 1. The title product isobtained with a yield de 87%.

C₁₅H₁₉NO₂ClF (MW=299.5).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.35 (t, 3H, J=7.0 Hz), 0.96 (t, 3H,J=7.0 Hz), 2.57 (m, 2H), 2.67 (m, 2H), 2.87 (q, 2H, J=7.0 Hz), 3.16 (q,2H, J=7.0 Hz), 4.00 (se, 1H, J=8.0 Hz), 5.02 (d, 1H, J=7.2 Hz), 7.27 (t,1H, J=8.0 Hz), 7.50 (t, 1H, J=8.0 Hz), 7.65 (t, 1H, J=8.0 Hz).

SM-ESI: 300 (MH⁺).

Step 4:trans-3-(dioxoisoindoline-2-yl)-N,N-diethyl-1-(2-fluoro-3-chlorophenyl)-cyclobutanecarboxamide(F7a)

Identical to step 4 described for Example 6. The title product isobtained with a yield de 45%.

C₂₃H₂₂FClN₂O₃ (MW=428.5).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.29 (t, 3H, J=6.8 Hz), 1.04 (t, 3H,J=6.8 Hz), 2.94-3.04 (m, 4H), 3.22-3.28 (m, 4H), 4.61 (qu, 1H, J=8.8Hz), 7.35 (t, 1H, J 8.0 Hz), 7.54 (t, 1H, J=8.4 Hz), 7.62 (t, 1H, J=7.2Hz), 7.83 (s, 4H).

SM-ESI: 429 (MH⁺).

Step 5:trans-3-amino-N,N-diethyl-1-(2-fluoro-3-chlorophenyl)-cyclobutanecarboxamide(1g)

Identical to step 5 described for Example 6. The title product isobtained with a yield de 93%.

C₁₅H₂₀FClN₂O (MW=298.5).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.27 (t, 3H, J=6.8 Hz), 0.97 (t, 3H,J=6.8 Hz), 2.08 (m, 2H), 2.88-2.94 (m, 4H), 3.17-3.25 (m, 3H), 7.26 (t,1H, J=8.0 Hz), 7.44-7.49 (m, 2H). The signal corresponding to the H inNH₂ is not visible on the spectrum.

SM-ESI: 299 (MH⁺).

Maleate of the Title Compound

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 179° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.26 (t, 3H, J=6.8 Hz), 0.99 (t, 3H,J=6.8 Hz), 2.60 (m, 2H), 2.91-3.00 (m, 4H), 3.20 (q, 2H, J=6.8 Hz), 3.34(s, 1H), 3.61 (qu, 1H, J 8.4 Hz), 6.02 (s, 2H), 7.32 (t, 1H, J=8.0 Hz),7.52-7.57 (m, 2H), 7.97 (s, 3H).

¹³C-NMR (DMSO d₆, 100 MHz) δ (ppm): 12.15, 12.21, 36.19, 40.08, 40.56,41.16, 43.81, 120.16, 125.59, 127.11, 129.12, 132.00, 136.11, 153.74,156.22, 167.19, 169.48.

% Theoretical: C, 55.01; H, 5.83; N, 6.75.

% Found: C, 54.73; H, 5.98; N, 6.46.

EXAMPLE 9trans-3-amino-N,N-diethyl-1-(2,5-difluorophenyl)-cyclobutanecarboxamide(1h) Step 1: cis-3-hydroxy-1-(2,5-difluorophenyl)-cyclobutanecarboxylicacid (B8)

Identical to step 1 described in 1 by using 2,5-difluorophenylaceticacid as the starting acid. The title product is obtained in the form ofa white solid (yield=69%).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.55 (m, 2H), 2.71 (m, 2H), 3.94 (qu,1H, J=7.2 Hz), 5.32 (s, 1H), 7.12-7.23 (m, 2H), 7.41 (m, 1H), 12.48 (s,1H).

Step 2: 4-(2,5-difluophenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C8)

Identical to step 2 described in Example 1. The title product isobtained in the form of a colourless oil (yield=91%).

C₁₁H₈F₂O₂ (MW=210).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 2.77 (m, 2H), 2.98 (m, 2H), 5.01 (s,1H), 6.93-7.08 (m, 3H).

SM-ESI: 228 (M+NH4⁺).

Step 3:cis-3-hydroxy-N,N-diethyl-1-(2,5-difluorophenyl)-cyclobutanecarboxamide(D8a)

Identical to step 3 of Example 1. The title product is obtained in theform of a white solid (yield=100%).

C₁₅H₁₉NO₂F₂ (MW=283).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.56 (t, 3H, J=6.8 Hz), 1.09 (t, 3H,J=6.8 Hz), 2.82 (m, 5H), 2.95 (q, 2H, J=6.8 Hz), 3.31 (q, 2H, J=6.8 Hz),4.32 (qu, 1H, J=7.2 Hz), 6.91-7.11 (m, 3H).

SM-ESI: 284 (MH⁺).

Step 4:trans-3-azido-N,N-diethyl-1-(2,5-difluorophenyl)-cyclobutanecarboxamide(E8a)

Identical to step 4 described in 1. The title product is obtained in theform of a colourless oil (yield=76%).

C₁₅H₁₈N₄OF₂ (MW=308).

¹H-NMR (CDCl₂, 400 MHz) δ (ppm): 0.51 (t, 3H, J=7.2 Hz), 1.10 (t, 3H,J=7, 2 Hz), 2.51 (m, 2H), 2.98 (q, 2H, J=7.2 Hz), 3.19 (m, 2H), 3.32 (q,2H, J=7.2 Hz), 4.02 (qu, 1H, J=8.0 Hz), 6.90-7.04 (m, 3H),

SM-ESI: 309 (MH⁺).

Step 5:trans-3-amino-N,N-diethyl-1-(2,5-difluorophenyl)-cyclobutanecarboxamide(1h)

Place 1 eq of compound (E8a) in a flask and dissolve in 20 volumes ofTHF. Stir under an atmosphere of nitrogen then add 1 volume of water and1.5 eq of triphenylphosphine.

Carry on stirring overnight. Evaporate the THF under reduced pressureand take up the residue obtained with water and extract twice with DCM.Dry the organic phases on MgSO₄, filter then evaporate the solvent underreduced pressure. The oil obtained is purified by flash chromatographywith the following mixture as the eluant: DCM/methanol/NH₄OH 95:4.5:0.5.The title product is obtained in the form colourless oil with a yield de97%.

C₁₅H₂₀N₂OF₂ (MW=282).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.51 (t, 3H, J=6.8 Hz), 1.10 (t, 3H,J=6, 8 Hz), 2.15 (m, 2H), 2.99 (q, 2H, J=6.8 Hz), 3.16 (m, 2H), 3.32 (q,2H, J=6.8 Hz), 3.52 (qu, 1H, J=8.0 Hz), 6.85-7.02 (m, 3H). The signalcorresponding to the H in NH₂ is not visible on the spectrum.

SM-ESI: 283 (MH⁺).

Maleate of the Title Compound

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 184° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.31 (t, 3H, J=6.8 Hz), 0.99 (t, 3H,J=6.8 Hz), 2.58 (m, 2H), 2.93-2.97 (m, 4H), 3.20 (q, 2H, J=6.8 Hz), 3.34(s, 1H), 3.59 (qu, 1H, J=8.4 Hz), 6.02 (s, 2H), 7.13-7.30 (m, 2H),7.49-7.53 (m, 1H), 7.97 (s, 3H).

¹³C-NMR (DMSO d₆, 100 MHz) δ (ppm): 12.04, 12.15, 36.08, 40.00, 40.61,41.20, 43.48, 114.90, 117.2, 124.37, 132.1, 136.00, 154.6, 157.05,157.13, 159.51, 167.12, 169.41.

% Theoretical: C, 57.28; H, 6.07; N, 7.03.

% Found C: 57.21; H, 6.01; N, 6.66.

EXAMPLE 10trans-3-amino-N,N-diethyl-1-(3,5-dichlorophenyl)-cyclobutanecarboxamide(1i) Step 1: cis-3-hydroxy-1-(3,5-dichlorophenyl)-cyclobutanecarboxylicacid (B9)

Identical to step 1 described in 1 by synthesizing3,5-dichlorophenylacetic acid in advance after which it is used as thestarting acid. The title product is obtained in the form of a whitesolid (yield=50%).

C₁₁H₁₀Cl₂O₃ (MW=261).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 2.53 (m, 2H), 2.77 (m, 2H), 3.87 (qu,1H, J=7.4 Hz), 5.23 (s, 1H), 7.38 (m, 2H), 7.51 (m, 1H), 12.62 (s, 1H).

SM-ESI: 259.

Step 2: 4-(3,5-dichlorophenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C9)

Identical to step 2 described in Example 1. The title product isobtained in the form of a colourless oil (yield=87%).

C₁₁H₈Cl₂O₂ (MW=243).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 2.72 (m, 2H), 2.88 (m, 2H), 4.99 (s,1H), 7.21 (m, 2H), 7.34 (m, 1H).

SM-ESI: 244 (MH⁺).

Step 3:cis-3-hydroxy-N,N-diethyl-1-(3,5-dichlorophenyl)-cyclobutanecarboxamide(D9a)

Identical to step 3 of Example 1. The title product is obtained in theform of a white solid (yield=100%).

C₁₅H₁₉Cl₂O₂N (MW=316).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.77 (t, 3H, J=7.2 Hz), 1.09 (t, 3H,J=7.2 Hz), 2.58 (s, 1H), 2.75 (m, 4H), 2.88 (q, 2H, J=7.2 Hz), 3.32 (q,2H, J=7.2 Hz), 4.34 (qu, 1H, J=7.6 Hz), 7.20-7.27 (m, 3H).

SM-ESI: 316.

Step 4:trans-3-azido-N,N-diethyl-1-(3,5-dichlorophenyl)-cyclobutanecarboxamide(E9a)

Identical to step 4 described in 1. The title product is obtained in theform of a colourless oil (yield=79%).

C₁₅H₁₈N₄OCl₂ (MW=341).

¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 0.67 (t, 3H, J=7.2 Hz), 1.12 (t, 3H,J=7.2 Hz), 2.40 (m, 2H), 2.87 (q, 2H, J=7.2 Hz), 3.15 (m, 2H), 3.36 (q,2H, J=7.2 Hz), 3.99 (qu, 1H, J=7.6 Hz), 7.13 (m, 2H), 7.25 (m, 1H).

SM-ESI: 341.

Step 5:trans-3-amino-N,N-diethyl-1-(3,5-dichlorophenyl)-cyclobutanecarboxamide(1i)

Identical to step 5 of Example 9. The title product is obtained in theform colourless oil with a yield de 78%.

C₁₆H₂₀N₂OClF (MW=283).

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.58 (t, 3H, J=7.2 Hz), 1.00 (t, 3H,J=7.2 Hz), 1.90 (s, 2H), 2.07 (m, 2H), 2.85 (m, 4H), 3.11 (qu, 1H, J=8.0Hz), 3.25 (q, 2H, J=7.2 Hz), 7.23 (m, 2H), 7.48 (m, 1H).

SM-ESI: 283.

Maleate of the Title Compound

Salification of the previous compound by means of maleic acid leads toobtaining Maleate of the title compound in the form of a white powder.

Mp: 180° C.

¹H-NMR (DMSO d₆, 400 MHz) δ (ppm): 0.57 (t, 3H, J=6.8 Hz), 1.02 (t, 3H,J=6.8 Hz), 2.58 (m, 2H), 2.85-2.96 (m, 4H), 3.28 (q, 2H, J=6.8 Hz), 3.54(qu, 1H, J=8.4 Hz), 6.02 (s, 2H), 7.28 (s, 2H), 7.56 (s, 1H), 7.99 (s,3H).

¹³C-NMR (DMSO d₆, 100 MHz) δ (ppm): 11.96, 12.19, 36.83, 39.20, 41.10,46.2, 124.03, 126.38, 134.50, 136.02, 146.66, 167.12, 170.04.

% Theoretical: C, 52.91; H, 5.61; N, 6.50.

% Found: C, 53.01; H, 5.53; N, 6.11.

The following examples make it possible to understand the inventionbetter without in any way limiting its scope.

The compounds of general formula (1) as well as a pharmaceuticallyacceptable source present remarkable pharmacological properties: theyare generally more powerful than ketamine as NMDA channel blockers atthe same time as having fewer unwanted effects on the central nervoussystem than ketamine.

We examined the effects of the compounds of the invention on inhibitionof the NMDA current in Xenope (Xenopus laevis) expressing recombinanthuman NMDA receptors constructed from NR1 and NR2B sub-units. Thecurrents produced by stimulation of these receptors by means ofendogenous agonists were studied according to the two electrode voltageclamp technique reported by Planells-Cases et al., 2002, J. Pharmacol.Exp. Ther., 302, 163-173.

Protocol: ovocytes were surgically removed from adults xenopes,enzymatically defolliculated and stored at 17° C. in a solutioncontaining: 96 mM of NaCl, 2 mM of KCl, 1 mM of MgCl₂, 1.8 mM of CaCl₂and 5 mM of HEPES at pH 7.5 (NaOH) and 50 mg/L of gentamycin (Heusler etal., 2005, Neuropharmacology, 49, 963-976). Complementary DNA (cDNA)coding for the NR1 sub-unit was cloned by PCR using primers targeted forstart and end codons in the published sequence (Genebank access numberM_007327). cDNA coding for the NR2B sub-unit was synthesised byEurogentec (Seraing, Belgium) according to the published sequence (genebank access number NM_000834). The NR1 and NR2B cDNA was then sub-clonedin the pGEMHE high expression carrier for in vitro transcription ofcDNA. cRNA coding for NR1 and NR2B was prepared according to the methoddescribed by Heusler et al. (already cited). Aliquots of the cRNAsolution were injected into the ovocytes (20-500 pg/ovocyte for NR1 and40-1000 pg/ovocyte for NR2B). Each ovocyte was injected with 100 nL of asolution containing: 4 mM of Na⁺BAPTA (pH 7.2) in order to block allresidual chlorine currents. After stabilisation, NMDA currents wereactivated by superfusion of glutamate and glycine each at aconcentration of 10 μM. The compounds to be tested were then superfusedin a Ringer Ba⁺⁺ solution at increasing concentrations in the presenceof glutamate and glycine (4 to 5 concentrations were tested perovocyte). The concentration-response codes obtained are analysed foreach ovocyte by non-linear regression and a pIC₅₀ value was calculated.pIC₅₀ designates the negative logarithm of the compound concentrationtested needed to reduce the amplitude of the NMDA current by half.

Results: table 1 below gives the pIC₅₀ values for certain compounds ofthe invention. It emerges that, under the test conditions compounds(1a1), (1b), (1c), (1d) and (1e) block the NMDA current in aconcentration-dependant manner and are more powerful than ketamine, theNMDA antagonist used clinically.

TABLE 1 Inhibition of NMDA Compound current pIC₅₀ 1a1 6.3 1b 6.3 1c 6.81d 6.4 1e 7.1 ketamine 6.1

Given the low bioavailability of ketamine by oral route, we chose theintraperitoneal (ip) route as the sole administration route for in vivoexperiments. The analgesic activity of compounds of formula (1) and ofketamine, chosen as the reference compound, were determined in aclassical acute inflammatory pain model, intradermal injection offormaldehyde (Bardin et al., 2001, Eur. J. Pharmacol., 421, 109-114).

Protocol: Male rats (Sprague-Dawley Iffa Credo, France) were placed inPlexiglas observation boxes above an angled mirror to facilitateobservation of their hind paws. After 30 minutes of acclimatisation, theanimals received a formaldehyde injection diluted to 2.5% on the plantarsurface of the right hind paw. Injection of formaldehyde producesbehavioural responses which occur in two phases:

-   -   an early phase, 0 to 5 minutes after injection of formaldehyde,        corresponding to stimulation of the receptors specialised in the        transmission of nociceptive stimuli;    -   a late phase which occurs 20 to 30 minutes after injection. This        phase corresponds to stimulation of the receptors by        inflammatory mediators and/or to hyperexcitation of the dorsal        horn induced during the first phase. This later phase therefore        brings into play central sensitisation of the pain        neurotransmission system in which the glutamate/NMDA system        plays a major role. As a result of this, the pain in the second        phase is more representative of neuropathic pain than the pain        which occurs during the first phase. For this reason, only        results obtained in this later phase are taken into        consideration in this application.

We selected licking of the paw which received the injection as abehavioural parameter for quantification of pain and chose as theobservation periods those periods corresponding to the later phase (inother words, 22.5-27.5 min post-formaldehyde injection). During this 5min phase, animals are observed every 30 seconds in order to notewhether or not the animal is licking the “injected” paw; thus themaximum score is 10. The products of the invention or the carrier areadministered by ip route 15 min prior to the injection of formaldehyde.

Results: In this test, the compounds of formula (1a1) and (1e),representative of compounds of the invention, have remarkable analgesiceffect (table 2). Thus the minimum significant dose (MSD, the doseneeded to significantly reduce licking of the injected paw) for thecompounds of formula (1a1) and (1e) is less than that for ketamine.Another advantage of the compounds of formula (1a1) and (1e) compared toketamine relates to the amplitude of the analgesic effect. In fact wenote that at a dose of 40 mg/kg, paw licking is completely inhibitedwith compounds (1a1) and (1e) whereas it only reaches a 74% reductionwith ketamine. Compounds (1a1) and (1e) are therefore more powerful andmore effective than ketamine.

TABLE 2 Paw licking MSD % reduction Compound (mg/kg) at 40 mg/kg 1a1 10100 1e 10 100 ketamine 40 75

To summarise, the analgesic effect of compounds (1a1) and (1e),representative of compounds of formula (1), is higher than that producedby ketamine in the acute inflammatory pain model in the rat.

We also show that the compounds of the invention have an antidepressantactivity in vivo. The antidepressant activities of compounds of formula(1) and of ketamine were determined in a forced swimming model in therat, a model that is widely used as it is predictive of antidepressantactivity in humans.

Protocol: Male rats (Sprague-Dawley Iffa Credo, France) were placed in acylinder (height 45 cm and diameter 20 cm) filled with water at 25°C.±0.5° C. up to a height of 17 cm. This height allows the rats to swimor to float without their paws touching the base of the cylinder. 24hours before the test day, the rats are placed in the cylinder for 15min, after which time they no longer attempt to escape and remainimmobile at the surface. On the test day, the compound to be tested orthe carrier is injected (ip) into the animal which is placed in thecylinder 30 min later. The duration of immobility (defined when the ratsimply floats and only makes small movements to stay at the surface) ismeasured with an accuracy of 0.1 s for 5 minutes.

Results: In the forced swimming test, the compounds of formulas (1c) and1(e), representative of the series, significantly reduce the animal'simmobility time. When the ED₅₀ are compared, that is the doses whichreduce immobility time by half relative to control animals, we find thatthese are lower than for ketamine for compounds (1c) and 1(e), see Table3. Similarly the amplitude of the anti-immobility effect observed at adose of 20 mg/kg is greater with compounds (1c) and 1(e) than thatobtained with ketamine.

TABLE 3 Immobility time ED₅₀ % reduction Compound (mg/kg) at 20 mg/kg 1c13 83 1e 15 77 ketamine 20 50

To summarise, compounds (1c) and 1(e), representative of compounds offormula (1), are more powerful and more effective than ketamine in atest predicting antidepressant activity.

We have already highlighted the importance of normalising the NMDAreceptor function, in other words blocking its excessive activitywithout interfering, or interfering as little as possible, with itsnormal physiological functioning. As a marker of the interaction betweenthe products of the invention and the normal functioning of the NMDAreceptors, we chose the pre-pulse inhibition test for the jolt reflex(PPI). This test represents a measurement of the organism's capacity tofilter non-essential information. Non-competitive and competitiveantagonists as well as channel blockers reduce PPI in the rat(Depoortere et al., 1999, Behav. Pharmacol., 10, 51-62), such areduction being considered to be predictive of the psychotomimeticeffects of NMDA antagonists in humans.

Protocol: Male rats (Sprague-Dawley Iffa Credo, Les Oncins, France) wereplaced in 18.4 cm by 8.8 cm diameter cylinders resting on a base belowwhich a piezoelectric accelerometer is fixed to act as a detector of thejolt reaction. This is enclosed in a box with a loudspeaker attached tothe ceiling to deliver sound pulses and pre-pulses, and is acousticallyisolated (SR LAB, San Diego Instruments, San Diego, USA). All the eventsare controlled by means of software. The animals first undergo a 13minute pre-test to habituate them to the procedure and to eliminate ratswhich do not respond to a series of minimum reaction criteria. Threetypes of sound stimuli (white noise) are delivered; 1) a pulse of 118 dB(P, duration 40 msec); 2) a pre-pulse of 78 dB (duration 20 msec)followed by a pulse of 118 dB (pP); and 3) no pre-pulse or pulse (NP).The interval between the beginning of the pre-pulse and the beginning ofthe pulse is 100 msec, with background noise at 70 dB. The jolt reactionis recorded for 100 ms, 100 ms after the beginning of the stimulus (pPor NP) by a numerical/analogue acquisition card (12 bits). The sessionstarts with a stimulus-free period of 5 min after which animals areexposed to 10 P (separated on average by 15 s and intended to stabilisethe jolt reaction). The reactions recorded with these 10 P are not usedfor the calculation. After this, 10 P, 10 pP and 3 NP are delivered in asemi-random order with an average interval of 15 s in between. At theend of this pre-test, rats undergo an ip injection of the compounds tobe tested or physiological serum as a control and are returned to theircages. The actual test session (similar on every point to the pre-test)is carried out 60 minutes later. The percentage inhibition of thepre-pulse is calculated using data from this test session according tothe formula:(median amplitude P−median amplitude pP)×100/(median amplitude P).

Results: According to FIG. 1 in the appendix, it appears that compound(1a1) does not disrupt inhibition of the jolt reflex induced by thepre-pulse (PPI) except from a dose of 20 mg/kg. Nevertheless,surprisingly the reduction in PPI is much less pronounced than thatobserved with ketamine. In fact at a dose of 20 mg/kg ip, ketamine leadsto the total disappearance of PPI whereas compound (1a1) only causes a30% reduction. The PPI reduction nonetheless remains modest even at adose of 40 mg/kg. Consequently compound (1a1) has a clearly lesspronounced tendency than ketamine to cause side effects of centralorigins.

In summary, the compounds of the invention possess analgesic andantidepressant activity that is superior to that of ketamine in theanimal model described above. Surprisingly the compounds of theinvention only cause very moderate central effects. It therefore emergesfrom these experiments that the risk/benefit ratio of the compounds ofthe invention is clearly more favourable than that of ketamine. As aresult of this, the compounds of the present invention as well aspharmaceutical compositions containing a compound of general formula (1)as the active principle or one of its pharmaceutically acceptable saltsare potentially useful as medications, particularly in the treatment ofcertain diseases such as, for example, depression and pain, especiallyacute or chronic pain, areas in which therapeutic needs are not fullymet and for which the discovery of new treatments is therefore highlydesirable.

The invention claimed is:
 1. Compound of the following general formula(1):

or pharmaceutically acceptable salt or solvate thereof, wherein: X₁represents a hydrogen atom or fluorine atom; X₂ is a hydrogen atom orfluorine atom or chlorine atom; R1 represents a hydrogen atom orfluorine atom or chlorine atom or methyl group or methoxy group or cyanogroup; and R2 represents independently or together a methyl group orethyl group.
 2. Compound according to claim 1, wherein: X₁ represents ahydrogen atom or fluorine atom; X₂ is a hydrogen atom or fluorine atomor chlorine atom; R1 a hydrogen atom or fluorine atom or chlorine atomor methyl group or methoxy group or cyano group; R2 is an ethyl group.3. Compound according to claim 1, chosen from among the followingcompounds: trans-3-amino-N,N-diethyl-1-phenylcyclobutanecarboxamide,trans-3-amino-N,N-dimethyl-1-phenylcyclobutanecarboxamidetrans-3-amino-N,N-diethyl-1-(2-fluorophenyl)-cyclobutanecarboxamide,trans-3-amino-N,N-diethyl-1-(3-methoxyphenyl)-cyclobutanecarboxamide,trans-3-amino-N,N-diethyl-1-(3-fluorophenyl)-cyclobutanecarboxamide,trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)-cyclobutanecarboxamide,trans-3-amino-N,N-diethyl-1-(3-methylphenyl)-cyclobutanecarboxamide,trans-3-amino-N,N-diethyl-1-(3-cyanophenyl)-cyclobutanecarboxamide,trans-3-amino-N,N-diethyl-1-(2-fluoro-3-chlorophenyl)-cyclobutanecarboxamide,trans-3-amino-N,N-diethyl-1-(2,5-difluorophenyl)-cyclobutanecarboxamide,trans-3-amino-N,N-diethyl-1-(3,5-difluorophenyl)-cyclobutanecarboxamide,andtrans-3-amino-N,N-diethyl-1-(3,5-dichlorophenyl)-cyclobutanecarboxamide.4. A method for the treatment of depression which comprisesadministering to a patient in need thereof an effective amount of acompound according to claim
 1. 5. A method for the treatment of pain dueto excessive nociception, or neuropathic pain which comprisesadministering to a patient in need thereof an effective amount of acompound according to claim
 1. 6. Pharmaceutical composition comprisingat least one compound of general formula (1) according to claim 1, andat least once pharmaceutically acceptable excipient.
 7. A method for thetreatment of depression which comprises administering to a patient inneed thereof an effective amount of a pharmaceutical compositionaccording to claim
 6. 8. A method for the treatment of pain due toexcessive nociception, or neuropathic pain which comprises administeringto a patient in need thereof an effective amount of a pharmaceuticalcomposition according to claim
 6. 9. Pharmaceutical compositionaccording to claim 6, which is formulated for oral administration. 10.Pharmaceutical composition according to claim 6, which is formulated fortopical administration.
 11. Pharmaceutical composition according toclaim 6, in the form of a daily dosage unit of a compound of generalformula (1) between 1 and 1000 mg.
 12. Method for the preparation ofcompounds of general formula (1) as defined in claim 1, wherein asecondary amine of formula (R2)₂NH is reacted with a compound of formula(C)

to give the compound of formula (D)

and the compound of formula (D) is then converted into an amine offormula (1), wherein R1, R2, X₁ and X₂ are as defined in claim
 1. 13.Synthesis intermediates of formula (D)

wherein X₁ represents a hydrogen atom or fluorine atom; X₂ is a hydrogenatom or fluorine atom or chlorine atom; R1 represents a hydrogen atom orfluorine atom or chlorine atom or methyl group or methoxy group or cyanogroup; and R2 represents independently or together a methyl group orethyl group.
 14. Synthesis intermediates of formula (C)

wherein X₁ represents a hydrogen atom or fluorine atom; X₂ is a hydrogenatom or fluorine atom or chlorine atom; and R1 represents a hydrogenatom or fluorine atom or chlorine atom or methyl group or methoxy groupor cyano group.